The objective of this research application is to synthesize analogs of the cylic undecapeptide cyclosporin as potential agents for treatment of arthritis. Cyclosporin, a novel immunosuppressive agent that inhibits certain T-cell populations while not suppressing humoral immunity, has been shown to inhibit development of experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) in animals. Cyclosporin has not been synthesized and nothing is known about the relationships between structure and its anti-arthritis and immunosuppressive activities. The objectives of this proposal are to: 1) synthesize the novel amino acid, 2S-methylamino-3R-hydroxy-4R-methyl-6E-octenoic acid; (2) synthesize MeThr5-cyclosporin, a model for the 33-membered ring system. Combine 1 and 2 to synthesize cyclosporin; (3) synthesize semisynthetic analogs of cyclosporin from the native molecule; (4) determine the activities of the semisynthetic and synthetic analogs on 3 in vitro assays to measure the immunosuppressive activities of the analogs and three in vivo assays (EAE, AA and murine SLE) to measure effects of analogs on established animal assay systems.